Webneb schulemann



, Patented Nov. 6, 1928.

UNITED, STA

WERNER scnunnmmn, or vo'nwm'xnn,

vGIEZZB'MAINY, ASSIGNORS, BY MESNE ASSIGNMEN T TS, TO WINTHROP CHEMICAL COM- AND KURT MEISENBORG; F ELBERFELD,

PANY, INC 0] YORK, N; Y., A CORPORATION OF NEW YORK.,

rnanmaonu rroan comrotmn.

ll'o Drawing. Application filed February 20, 1925,

in which R is an unsaturated. alicyclic radi I Z cle and R is a saturated .or unsaturatel alkyl residue, or their derivatives, as for example the corresponding acyl chlorides, esters, amines, amino esters, nitriles etc. are converted into the barbituric acids according to the j usual methods employed for the preparation of the barbituric acids and their derivatives alkylated orarylated on the carbon. It is also possible to roceed b first introducing the second substituent in t e barbituric acids substituted in the 5-position by one of the above mentioned substituentsor into suitable intermediate roducts for the preparationof these barbituric acidsand converting the intermediate products so obtained into the barbituric acids. In this method the mono-substituted barbituric acids mentioned, or their intermediateproducts, may be prepared either from mono substituted malonic esters or cyanacetic 1 esters or from their derivatives; or also they 40 may be obtained by introducing one of the \s ubstituents namedv into the barbituric acids or their intermediate roducts..

lace with remarkable ease and good ields. teric hindrances are not noticeable. ert'ain of the new sedatives as for instance the, A -1.2-cyclohexenylethylbarbituric acid de- -.scribed in Example 3 are-unsymmetrlcally f constituted. Y i

The new compounds are generally whitishv c i eroducts easil soluble-in a dilute" f sodium car nate solution, acetone, acetic r carried out as above, yields the The preparation 0 the new products takes parts b Jweig Serial No. 10,657, and i Germany March 21,1924.

acid ester and alcohol and soluble with difiicultyin ether, benzene and water.

E'wample 1.-470 parts by weight of nionoethylmalonic ester are introduced with ice' cooling.and stirring into a solutionof 57.5 parts by weight of sodium in 950 parts of absolute alcohol. The sodium monoethylmalonic ester formed is then gradually treated without ice cooling with 420 parts by weight of 1-brom-A-23-cyclohexene. The reac; tion mixture becomeswarm, sodium bromide se arates out and the mixture becomes neutral a ter a short time. The sodium bromide is filtered ofi, the filtrate freed from alcohol by distillation, the residue taken up in water,

I siphoned oil, dried over calcium chloride and distilled in vacuo. A-QB-cyclohexenylethylmalonic esterv boils at 1 19-151 C. at 12 mm. 46 parts by weight of sodium are dissolved in 50 parts of alcohol, 90 parts by weight of ureaareintroduced into the cooled sodium ethylate solution and after this is dissolvedthe mixture is treated with 270 parts by weight of 4|-2.3 cyclohexenylethylmalonic ester. The reaction mixture is boiled for 6 hours, freed from alcohol by vacuum distillation, taken up in water and the A -2.3- cyclohexenyleth lbarbituric acid of a meltingdpoint 172 f is precipitated with acetic aci I Example 2.500 parts by weight of monoallylmalonic ester are introduced with stirring and ice cooling into a solutiorf of 57.5 parts by weight of sodium in 950 parts of absolute alcohol. The sodium monoall'ylmalonic ester-formed is then treated graduall without icecooling with 420 parts by'weight of 1-brom-/l-2.3-cyclohexene. The reaction 'mixture bgcomes warm, sodium bromrdeseparating out and is neutral when the maternal has been added. The working u which is -2.3-cyclohexenylallylmalonic ester boiling at 150-162 C. at 8 mm. 46 parts by weight'of sodium are dissolved in 850 parts of absolute alcohol, 'ht of urea are introduced into the coo ed so ium ethylate solution and'after all has dissolved the mixture is treated with 280 parts by weight of 4]- 2.3 cyclohexenylallyhnalonic ester.- The reaction mixture is boiled for 6 hours under a'reflux condenser. The working up is carried 'out in the same manner as in Example 1 and yielded-2.3- cyclohexenylallylbarbituric acid melting at 149 C. l i

E mam -1.2cyclohexenylcyanacetic acid ester are introduced with stirring and ice cooling into a solution of 9Q parts by weight of sodium in 1500 parts. of absolute alcohol. The sodium l-L2-cyclohexen lc yanacetic acid ester formed is then gra ually treated without ice cooling with 7 50 parts by weight of ethyl iodide. The reaction mixture becomes warm, sodium iodide separating, out and the whole isneutral after a short time. The working up carried out as in Example 1 yields Li-LQ- cyclohexenylethylcyanacetic acid ester boiliri'g at 125 C. at 4 mm. 72 parts by weight of sodium are dissolved in 1086 parts by weight of absolute alcohol and boiled for 3% sulfate, then 221 parts hours with285 parts by weight of guanidine by weight of 41-12- v cyclohexenylethylcyanacetic acid ester' are added and boiling is continued for a further tilling Weight of dilute sulfuric acid and thenA -1.2

12 hours. The residue remaining after disoff the alcohol is boiled with 10 times its cyclohexenylethylbarbituric acid which separates out is recrystallized fromhot water. The melting pointis 17 0 C.

crystalline product, easily soluble in dilute sodium carbonate solution, acetone acetic acid ester and alcohol and soluble with difficulty in ether, benzene and water. The product has most probably the formula? i 1H H:

. l H-N In place of /J-1.2 cyclohexenylcyanacetic I acid ester" A-LQ-methylcycl heXenyl or V 4l-12-eyclopentenylcyanacetic acid ester ma be used in a similar manner. u

' e hourswith tit wdmple Lf- Into a mixture of 1200-parts by weight of cyclopentenylcyanacetic acid ester and 7 30 parts by weight of ethylbromide a solution of 153 parts by weight of'sojdium in 3000 parts by weight of alcohol is intro-- mixture is warmed for v duced. The reaction several hours. on the water bath.- The workmg up ,carried out as in Example 1' yields 14..2rcyclopentenylethylcyanacetic acid ester boiling at 128 C; at 8 mm. 21,4 parts by weight of sodium are dissolved in 300 by weightpf absolute alcohol'and'boile for 95.1 parts by weight ofguane sulfate. Then 68 parts by weight of cyelteipentenylethylcyanacetic acid ester 'are jadd and is continued ior a. further 12 hours. The residue rem f after.

ofi the alcohol isoboiled with 10 times Jtsweight of, dilute sulfur c acid and the 2;; fir-772 parts ,by weight of The'new compound is generally a whitish arts" wh'ere R is an unsaturated alicyclic nucleus and R is a saturated or unsaturated alkyl residue, which are generally whitish crystalline products being easily soluble in. a dilute solution of sodium carbonate and soluble with difliculty in benzene and Water; and being valuable hypnotics, substantially as described.

arates out is recrystallized from i f the 2. The herein described new unsymmetrically disubstituted general formula wherein R represents a cyclohexenyl res idue and R represents a saturated or unsaturated alliyl residue, which are generally whitish crystallineproducts being easily soland soluble with difficult in benzene and Water; and being Valuab e hypnotics, substantiallv as described.

3. The herein descrlbed new unsymmetriuble in a dilute solution of sodium carbonate barbituric acids of the cally disubstituted barbituric acids'of the general formula:

benzene and water; and bein yaluable hyp-' notics, substantially as descri d.

4. The herein "described A-LQ-cyclohexeiiylethylbarbituric acid having most probab y thejormula:

. n n; zen-co 4 crys' illizingi from water in c at 1'20 C. being soluble with culty in benzene and water and being a valuable hypnotic, substantially as described.

Intestimopy whereof we have hereunto set our'hand s.

1 'WERNER SCHULEMAN KURT MEISENBUBG.

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